Research Projects in detail:

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1 AG Molecular Cardiology and Stem Cell Research, Clinic for Internal Medicine I Friedrich Schiller University Jena Prof. Dr. Maria Wartenberg Erlanger Allee 101, Jena Our research interests focus on signalling pathways leading to cardiovascular differentiation. We like to develop a new approach to generate cardiomyocytes from stem cells of different origin. Also we are interested to characterise cardiovascular progenitor cells and study which microenvironment and which signalling cascades conduct progenitor cells to differentiate into functional cardiomyocytes and endothelial cells as well. Our major research fields are: 1. Cardiovascular differentiation from embryonic stem cells / Redox-sensitive signalling pathways / Function of NAD(P)H oxidases in blood vessel and cardiomyocyte differentiation 2. Stem cell derived in vitro model systems/ replacement of animal experiments / in vitro models of cellular defence and inflammation / leucocyte differentiation from ES-cells 3. Induced pluripotent stem cells (ips-cells)/ generating ips-cells from fibroblasts or mesenchymal stem cells / isolation and characterisation of ips clones / regulation the embryonic gene expression. 4. Metabolic processes and differentiation/ effect of PPARγ on differentiation and proliferation Research Projects in detail: 1.1 Redox sensitive signalling pathways leading to cardiovascular differentiation The project was supported by SFB 604 "Multifunctional Signalling Proteins - Oligomeric Protein Complexes as Mediators of Cellular Regulation Processes" Embryonic stem (ES) cells spontaneously differentiate into blood vessels and cardiomyocytes. We and other groups pointed out that reactive oxygen species (ROS) act as second messengers in signalling cascades leading to cardiovascular differentiation. We study the interaction of NAD(P)H oxidases with receptor tyrosine kinase induced signalling cascades which influence vasculogenesis/angiogenesis and cardiomyocyte differentiation in a particularly controlled mechanism. Angiogenesis assay on Matrigel showed formation of capillary networks Immunofluorescence staining for Vasculogenesis, angiogenesis and Isolated cardiomyocytes detected by laser scanning confocal microscope (C-LSM ) ROS levels were measured using the fluorescent dye H2DCF-DA and recorded by C-LSM

2 1.2 Membrane potential changes and external electromagnetic field application control angiogenesis and pacemaker/cardiomyocyte differentiation in stem cells The project was supported by Deutsche Stiftung Herzforschung External modulation of the membrane potential induces signalling cascades in ES cells which control the differentiation of blood vessels cardiomyocytes and chondro-osteogenesis as well. We study the effect of external electromagnetic field pulses on stem cell differentiation. Induced membrane potential changes at multicellular spheroids following application of external electromagnetic field pulses; di-8-anneps and Confocal laser scanning microscopy. Induced membrane potential changes: Hyperpolarisation, 1,600 1,550 1,500 Ratio - Intensity 1,450 1,400 1,350 1,300 1,250 1,200 18,920 31,530 44,150 56,760 69,370 81,990 Time [s] 1.3 NAD(P)H -oxidases regulate angiogenesis and leukocyte differentiation The project was supported by the IZKF Jena ROS generated by the NADPH -oxidase enzyme complex may act as second messenger and can thus control cellular processes such as proliferation, differentiation, and gene expression. Aim of this study is to assess the impact of the NADPH-oxidases NOX1, NOX2, and NOX4 on the vascular and leukocyte differentiation using the murine in-vitro-differentiation model of the Embryoid Body (EB). Therefore, we established stem cell lines repressing NOX1, NOX2, or NOX4 expression by shrna technique. 2. In vitro models for cellular defence and inflammation: Testing the biocompatibility of biodegradable polymers in vitro The project was supported by Stiftung Forschung 3R, Swizerland Artificial implants are more and more common in clinical daily routine and were used in large diversity. This includes for instance dental prosthetics, bone reconstruction, artificial joints, vascular prosthetics and artificial heart valves. Recently biocompatible polymers and biodegradable polymers were developed. They have enormous potential in processing of artificial heart valves, artificial blood vessels, occluders etc. Biodegradable Polymers support healing process; they are able to degrade in a biological surrounding. In this project we use ES cell to cultivate an immuno- competent vascularised tissue (INFLAPLANTtissue) which is able to show a cellular response to specific materials which allows conclusions about the biocompatibility. Our INFLAPLANT-tissue approves the study of angiogenesis, differentiation of inflammatory cells and their migration next to the polymer material. Leukocytes indicated by CD68 immunohistochemistry (yellow) Angiogenesis indicated by PECAM-1 immunohistochemistry (red) in

3 interact with biodegradable polymers (blue). INFLAPLANT-tissue in co- culture with biodegredable polymers (blue) 3.1 Generation of induced pluripotent stem cells (ips-cells) We generate ips cells from human fibroblasts and adult mesenchymal stem cells. Our aim is to develop protocols for the induction of endothelial cells and cardiomyocytes from ips cells. PECAM-1 immunohistochemistry on a layer-culture from cells differentiated from human ips-cells Human Induced pluripotent stem (ips) cell colony cultured on mouse embryonic feeders 3.2 Effect of microenvironment on embryonic gene expression in ES-cells, human ASC and induced pluripotent stem cells. Embryonic genes (oct3/4, Nanog, Lin28, Sox) characterise pluripotency and plasticity in embryonic, adult stem cells and ips-cells after reprogramming. We intend to explain how the microenvironment of different stem cell types controls the expression of embryonic genes. 4. The effect of PPARγ (Peroxisome proliferator-activated receptor-γ) on differentiation and proliferation of endothelial cells and smooth muscle cells PPARγ affects pathways important in a variety of human diseases. Moreover, PPARγ agonists exert anti-inflammatory, anti-oxidative and anti-proliferative effects on vascular wall cells. We conclude that the activation or inhibition of PPARγ may have effects of the differentiation of endothelial cells, smooth muscle or cardiomyocytes. Furthermore, PPARγ agonists are likely to have atheroprotective properties. In a previous project we took part in a study investigating the effect of PPARα on cardiomyogenesis from murine ES-cells. In the actual project, which represents a translational collaboration between basic and clinical research, we seek to determine the effect of PPARγ agonists on endothelial and smooth muscle cell differentiation and proliferation in vitro and to compare this data with experimental findings from blood vessels in vivo. Other study objectives are: to identify the sites were PPARγ interacts with receptor tyrosine kinase pathways, to investigate if PPARγ inhibits NAD(P)H -oxidases and how this interaction takes place.

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